Rivaroxaban versus vitamin K antagonist treatment on the progression of coronary calcification: the IRIVASC-trial

Vitamin K antagonists (VKA) remain the only option of anticoagulation for people with mechanical valve replacement and due to their wider availability and lower acquisition costs, VKA’s remain widely used in low- and middle-income countries. It has been suggested that prolonged use of VKAs can increase the development of vascular and valvular calcification, though this effect has not been examined in larger randomized prospective trials. This investigator-initiated multicenter, prospective, randomized, open-label interventional trial randomized patients with baseline coronary or valvular calcification and an indication for prolonged oral anticoagulation therapy to Marcumar or Rivaroxaban. Patients were followed-up through repeat coronary computed tomographies to measure the progression of coronary and valvular calcification for up to 24 months. 192 patients were randomized between 2013 and 2018 to receive either Rivaroxaban or Marcumar and followed for up to 24 months. Coronary calcification significantly increased over time although there was no significant difference in progression between the groups after 12 and 24 months as measured by the Agatston score [360.7 (90.2; 1075.3) vs 380.4 (136.4; 1546.9) p = 0.69], the volume score [295.8 (93.0; 995.3) vs 335.5 (128.7; 1316.9) p = 0.95] and the mass score [58.5 (15.9; 172.0) vs 71.1 (24.8; 257.3) p = 0.5]. Dephosphorylated, uncarboxylated matrix Gla Protein (Dp-ucMGP) significantly decreased in the VKA group [Δ dp-uc MGP – 95.2 (− 554.1; 156.0) vs 231.3 (− 59.7; 388.1) p < 0.001]. There does not appear to be a relevant effect of vitamin K inhibition by the vitamin K antagonist marcumar upon coronary calcification.


Patients
We enrolled adults requiring long-term OAT according to current international guidelines for the treatment of atrial fibrillation (ACC/AHA/ESC-guidelines) and/or pulmonary embolism (ACCP/ESC guidelines) and being capable of taking either a DOAC or marcumar.Patients were included if a coronary or valvular calcification, or both exceeding an Agatston Score > 50 in at least one location as assessed by Mult-Slice-CT at screening was present.Exclusion criteria were intolerance of the imaging, an eGFR < 20 ml/min, serious life-limiting illness and cognitive dysfunction limiting compliance with study procedures.Patients in whom coronary artery calcification could not be reliably assessed including those with previous multi-vessel stents for coronary disease were also excluded 13 .

Imaging
For calcium scoring, non-contrast ECG-triggered multi-slice CT (MSCT) of the whole heart was performed in a step-and-shoot-technique, as recommended by current guidelines 14 .All CT scanners employed in the present study were at least 64-slice MSCT scanners dedicated for cardiac imaging (SOMATOM Definition Flash, Siemens, Forchheim, Germany and Aquilion Prime, Canon Medical Systems, Neuss, Germany).To achieve reproducible and comparable calcium scoring results, every scanner are separately calibrated with a dedicated calcium calibration phantom (Anthropomorphic Cardio CT Phantom, size 300 × 200 × 100 mm, QRM Quality Assurance in Radiology and Medicine GmbH, Moehrendorf, Germany).The same basic scan parameters (80 mAs, 120 kV, 3/0.75 mm slice thickness, with the same rotation time, collimation, and pitch) were used at all sites after a scout view from the tracheal bifurcation to the bottom of the heart silhouette with adaption to participants' physiques.
Imaging data were electronically transferred to a single dedicated post-processing and measurement workstation (SyngoCaScoring, Wizard; Siemens, Erlangen, Germany) for quantification of valvular and coronary calcification.Both valvular and coronary artery calcification (CAC) measurements were undertaken using dedicated software (Syngo MMWP, VA13A, Siemens, Erlangen, Germany).The volume score was determined by the calculated volume (Hounsfield units > 130 and a minimum size of 0.5 mm 3 ) based on isotropic interpolation 15 .The Agatston score was calculated by multiplying density and size of the calcified areas as previously described 16 .
In patients with single-vessel stenting, the stented area was manually excluded.In the event of poor quality data, or multiple stents, patients were excluded from further study participation.All measurements were performed by the same investigator with more than 10 years of experience in CAC scoring blinded to treatment randomization and the date of the examination.To improve intra-reader reproducibility, baseline and follow-up CT are presented to the reader immediately following each other in a random order.

Intervention
Following baseline investigations, including baseline blood sampling and storage, patients were randomly assigned in a 1:1 ratio to either VKA (phenprocoumon Marcumar (R), titrated to target INR 2-3) or rivaroxaban (Xarelto) 20 mg once daily for patients with atrial fibrillation with eGFR > 49 ml/min and 15 mg once daily for patients with eGFR of 15 to 49 ml/min.

Sample size and statistical analysis plan
The primary outcome was the progression of coronary and aortic valve calcification at 12 month.The follow-up time was prolonged to 24 month.
With a sample size of 95 per group (total population of 190), IRIVASC was powered to identify a difference in change of calcification of 96 units with a standard deviation of the change in volume score of 234 units between the groups, over 12 months with an 80% power using a type 1 error of 0.05 based on previous data measuring volume score change over 12 months in placebo treated patients with asymptomatic or mildly symptomatic aortic valve calcification 20 .
After confirming normality using a Shapiro-Wilk test, continuous baseline variables are presented as means (SD).Categorical variables are presented as number (%).
Log transformed outcome measurements were modeled using linear mixed models with fixed treatment effect (2 categories), time, log transformed baseline measurement, treatment-time interaction, and random intercepts

Discussion
IRIVASC is the first multicenter trial to prospectively compare the cardiovascular calcification effects of VKA and Rivaroxaban (DOAC) on the progression of coronary and aortic valve calcification over 24 months.Previous studies had raised concerns about an acceleration and premature occurrence of CVC in patients treated with VKA.In a cross-sectional analysis of standard CTC imaging, Bob et al. described higher levels of coronary artery calcification in patients using VKA 4 .Using serial intravascular ultrasound (IVUS) Andrews et al. noted that while VKA treatment did not promote plaque formation, it did encourage the development of plaque calcification 17 .Subsequent to these two observations, there have been only two further small prospective studies.Both proposed slower coronary plaque progression in patients treated with the DOACs rivaroxaban and apixaban compared with patients treated with the VKA warfarin 18,19 .The studies enrolled 97 and 56 patients respectively.However, the changes noted were modest in degree, requiring multiple adjustments despite randomization.Furthermore, their trials only reported a one year follow rather than the up to 2 years we are reporting in our study.Inconclusive results regarding VKA usage and premature calcification have been shown in 2 studies in dialysis patients 20,21 .However, generalizability of trial results in dialysis patients is limited due to their unique  pro-calcific environment.Hence, the IRIVASC trial adds important novel insights into the field due to study size, population and follow-up time.
Our data provide additional insight around the results of a recent randomized, placebo-controlled study of vitamin K supplementation in 400 people with asymptomatic aortic stenosis 22 .After 2 years, there was no difference in the rate of progression of the aortic valve calcification between the groups.While in this study, the  authors explored the effect of supplementation of Vitamin K2 on the progression of aortic valve calcification, our study examined the iatrogenic reduction of vitamin K through the use of the vitamin K antagonist warfarin.Taking these two studies together, despite the proposed molecular pathways, there does not appear to be a clinically relevant effect of vitamin K modulation on the progression of vascular calcification.
This finding is important for the future management of patients with valvular heart disease, in whom DOACs have shown insufficient efficacy 23 and also for people living in low and middle-income countries where vitamin K antagonist therapy is frequently used for decades.Although data about life-long VKA application and potential effects upon cardiovascular health effects are still missing, IRIVASC does not raise safety concerns regarding intermediate-term progression of CAC.
Our clinical findings seem to contrast with the commonly described VKA-mediated increased calcification though the decrease in dp-ucMGP.This is confirmed by the alteration in the levels of the precursor to vitamin K-dependent Matrix Gla Protein (MGP) which demonstrates the expected interference with the availability of the calcification-inhibitory system MGP.However, it seems that this downregulation of active MGP in the circulation does not translate to a faster progression of CVC in our specific patient cohort.This disconnect between the biochemical alterations and the clinical outcomes was also noted in the vitamin K supplementation study described above 24 .These findings and the recent failure of denosumab and alendronic acid, both effectors of bone turnover and used to treat osteoporosis, to slow valvular calcification 25 , suggest that the effect of vitamin K and the Matrix Gla Protein pathway on the progression of valvular and coronary artery calcification appear more complex and might not be the key clinical drivers.Whilst others have proposed that progression might be dose dependent 26 , the doses required to achieve this might limit its clinical applicability to specific subgroups and particularly high risk.On the other hand, whether vitamin K antagonism at higher levels than for formal anticoagulation might be effective on cardiovascular calcification is likely to be clinically irrelevant.
We must stress, that our study only evaluated the effect of VKA therapy on the development of CVC rather the development of plaque burden itself.As such Beyer et al. were able to show that VKA administration in patients with AF led to an increase in plaque burden compared to DOAC 27 therapy suggesting the effect may be related to other factors beside VKA's ability to interfere with vascular calcification.

Limitations
There are several limitations to highlight.Firstly, coronary or valvular calcification was an inclusion criterion such that IRIVASC could be considered a secondary prevention trial, perhaps limiting the relevance to the general population.Secondly, a large proportion of patients dropped out following the prespecified primary timepoint of 12 months scan, such that the study was underpowered at the time of the 24 months.The findings at 24 months should therefore be considered as exploratory.Finally, we did not record previous VKA usage or the time in treatment range for patients treated by VKA.

Conclusions
In conclusion, there does not appear to be a relevant effect of vitamin K inhibition by the vitamin K antagonist phenprocoumon (Marcumar®) upon coronary or aortic valve calcification over 24 months of treatment.The rate of calcification progression was similar to patients treated with rivaroxaban.Hence, the data do not support the long-held belief the VKA-induced accelerated progression of cardiovascular calcification is mediated by decreased MGP activity in humans.

Figure 2 .
Figure 2. Percentage change of Agatston Score (A), Mass Score (B) and Volume Score (C) over the two year follow-up.Data are shown as Mean with 95% CI. (ns non significant).

Table 1 .
Calcification parameters over two year follow up.